1398571-87-3

Upstream product

• 908027-64-5 6-chloro-3-[1-(3-chloro-2-fluorophenyl)-meth-(E)-ylidene]-1,3-dihydroindol-2-one 
• 108-94-1 cyclohexanone 
• 282735-66-4 (5R,6S)-5,6-diphenylmorpholin-2-one 
• 56341-37-8 6-chloro-2-oxindole 

Downstream Products

• 1410736-99-0 C₄₃H₄₄Cl₂FN₃O₄ 
• 1410737-05-1 C₃₈H₃₅Cl₂FN₂O₄ 
• 1410737-02-8 C₂₉H₃₂Cl₂FN₃O₃ 
• 1410737-29-9 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1R,4R)-4-hydroxycyclohexyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide trifluoroacetate 
• 1410737-08-4 C₂₄H₂₃Cl₂FN₂O₃ 
• 1410737-09-5 (4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycyclohexyl)-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5''-carboxylic acid 
• 1410737-13-1 C₃₁H₂₈Cl₂FN₃O₄ 
• 1410737-35-7 4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)benzoic acid trifluoroacetate 
• 1410737-38-0 C₂HF₃O₂*C₂₈H₃₀Cl₂FN₃O₄S 
• 1410737-15-3 C₃₁H₃₄Cl₂FN₃O₄ 
• 1410737-40-4 C₂HF₃O₂*C₃₀H₃₂Cl₂FN₃O₄ 
• 1410738-11-2 (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-methyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide 

Relevant academic research and scientific papers

Discovery of 4-((3′R,4′S,5′R)-6-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development

We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure-activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (Ki 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete and long-lasting tumor regression in vivo and is currently in phase I clinical trials for cancer treatment.

Design of chemically stable, potent, and efficacious MDM2 inhibitors that exploit the retro-mannich ring-opening-cyclization reaction mechanism in spiro-oxindoles

Inhibition of the MDM2-p53 protein-protein interaction is being actively pursued as a new anticancer therapeutic strategy, and spiro-oxindoles have been designed as a class of potent and efficacious small-molecule inhibitors of this interaction (MDM2 inhibitors). Our previous study showed that some of our first-generation spiro-oxindoles undergo a reversible ring-opening-cyclization reaction that, from a single compound in protic solution, results in an equilibrium mixture of four diastereoisomers. By exploiting the ring-opening-cyclization reaction mechanism, we have designed and synthesized a series of second-generation spiro-oxindoles with symmetrical pyrrolidine C2 substitution. These compounds undergo a rapid and irreversible conversion to a single, stable diastereoisomer. Our study has yielded compound 31 (MI-1061), which binds to MDM2 with Ki = 0.16 nM, shows excellent chemical stability, and achieves tumor regression in the SJSA-1 xenograft tumor model in mice.

SPIRO-OXINDOLE MDM2 ANTAGONISTS

Provided herein are compounds, compositions, and methods in the field of medicinal chemistry. The compounds and compositions provided herein relate to spiro-oxindoles which function as antagonists of the interaction between p53 and MDM2, and their use as therapeutics for the treatment of cancer and other diseases.